Objectives: Down syndrome (DS) is a genetic disorder that causes many problems for the affected person and his or her family. The present study aimed to investigate the effect of resilience training on the stress of mothers of students with DS. Methods: This study is a non-randomized clinical trial conducted on 36 mothers of students with DS studying at Shahid Rajaieh School, Tehran. They were selected by a convenience sampling method and divided into the control and intervention groups. Resilience skill training intervention was performed in ten sessions for the intervention group. The instruments used in the present study included a demographic questionnaire and a parenting stress index. Data were analyzed using SPSS software, version 18. Results: Before training resilience skills, no significant difference was observed between the mean stress scores in mothers of the intervention and control groups. After the training program, there was a significant difference between the mean stress scores of the two groups. Discussion: Training resilience skills can reduce stress in mothers of children with DS.